Summary / Abstract Our group has recently licensed a technology enabling the identification, isolation, and subsequent expansion of ?youthful? mesenchymal stem cells (MSCs) from elderly individuals. This population is characterized by small size and expression of stage specific embryonic antigen ? 4 (SSEA-4). Prior work indicates that small, SSEA-4+ (small(+)) MSCs, function in a manner similar to that of MSCs from young individuals. Moreover, studies suggest that while elderly MSCs contain a significant fraction of senescent cells expressing the senescence associated secretory phenotype (SASP), small(+) MSCs possess a secretory phenotype much more similar to young MSCs. As increasing evidence suggests that paracrine effects may be the most potent therapeutic mechanism of stem cells, and it is widely accepted that young stem cells are anti- inflammatory and immunomodulatory, it is reasonable to suggest that small(+) MSCs may be effective in the treatment of various chronic inflammatory diseases. The proposed studies test the feasibility of reducing an inflammatory reaction using small(+) MSCs isolated from elderly donors and expanded on a commercially available extracellular matrix that mimics the in vivo niche (CELLvo? Matrix). Feasibility will be determined in vitro using a lymphocyte proliferation assay, and a microarray to characterize the cytokine profile of small(+) MSCs relative to young or elderly MSCs. It is expected that small(+) MSCs will possess an anti-inflammatory cytokine profile, and will inhibit activated T-cells in the lymphocyte proliferation assay. If the results match expectations, small(+) MSCs may be used to address chronic inflammation in an animal model in a phase II study. As inflammation is key to the pathogenesis of most age-related diseases, this approach has the potential to slow or reverse the progression of any number of degenerative diseases for which no adequate treatments currently exist.